Hepatocellular carcinoma-linked AXIN1 mutations drive low Wnt/β-catenin activity enabling niche-independent growth and YAP/TAZ signaling

Abstract

AXIN1 organizes assembly of a destruction complex that degrades the transcriptional co-activator β-catenin, thereby preventing inappropriate Wnt/β-catenin signaling. In hepatocellular carcinoma (HCC), AXIN1 mutations associate with a poor-prognosis subtype distinct from β-catenin-mutant HCC (CTNNB1). To assess how AXIN1-deficiency drives HCC, we introduced HCC-associated AXIN1 and CTNNB1 mutations in human liver cancer cells and liver-derived organoids. We show that AXIN1 mutations activate Wnt/β-catenin signaling to varying but generally lower levels than CTNNB1 mutations. Strikingly, premature 5'-end stop codons do not yield knockout mutations but drive alternative translation of N-terminally truncated AXIN1 variants with partial suppressor activity. All AXIN1 variants enable liver progenitor organoids to grow without Wnt and R-spondin, indicating downstream Wnt/β-catenin activation. Additionally, Wnt/β-catenin signaling inversely correlates with YAP/TAZ-mediated signaling, leaving higher YAP/TAZ activity in AXIN1-mutant versus CTNNB1-mutant cells. Thus, AXIN1 mutations drive physiologically relevant Wnt/β-catenin activation, providing a permissive environment for YAP/TAZ signaling, thereby distinguishing them from CTNNB1 mutations.

Keywords: Cancer; Molecular interaction; Molecular network.